Research
My lab is interested in understanding mechanisms of neurodegeneration. The central theme is the identification of common pathways across the spectrum of these disorders (which include Alzheimer's and related diseases) that are relevant for both mechanistic insights and therapy. We focus both on ‘toxic’ processes that can be targeted to prevent neuronal death, and on regenerative processes that can be harnessed for repair. Using mouse models, we described the pathogenic role of the unfolded protein response (UPR) in neurodegeneration, which led to the discovery of the first small molecule - an inhibitor of this pathway - to prevent neurodegeneration in vivo. We have now identified repurposed drugs that are able to prevent neurodegeneration in mouse models of disease and are poised for clinical trials in humans. We also recently discovered the phenomenon of failure of synaptic repair processes in neurodegeneration and the underlying mechanisms: failure of another stress response involving 'cold shock' proteins, which we have successfully harnessed for neuroprotection. We aim to translate this research for new treatments for dementia.
Publications
New publications
- TrkB signaling regulates RBM3-mediated neuroprotection. Peretti DA, Smith, HL, Verity N, Humoud I, de Weerd L, Swinden DP, Hayes J and Mallucci GR. 2020 (accepted) Life Science Alliance.
- Developing Therapies for Neurodegenerative Disorders: Insights from Protein Aggregation and Cellular Stress Responses. Mallucci GR*, Klenerman D, Rubinsztein DC. Annual Review of Cell and Developmental Biology 2020. 36:X–Xb https://doi.org/ 10.1146/annurev-cellbio-040320-120625 *corresponding
- Targeting the kinase insert loop of PERK selectively modulates PERK signaling without systemic toxicity in mice. Hughes DT, Halliday M, Smith HL, Verity NC, Molloy C, Radford H, Butcher AJ, Mallucci GR. Science Signaling 2020 Aug11;13(644):eabb4749 doi:10.1126/scisignal.abb4749
- Astrocytic UPR causes non-cell autonomous neurotoxicity and represents new therapeutic target for neurodegenerative disease. Smith H, Freeman OJ, Butcher AJ, Holmqvist S, Humoud I, Schätzl T, Hughes DT, Verity NC, Swinden DP, Hayes J, de Weerd L, Rowitch DH, Franklin RJM, Mallucci GR. Neuron. 2020 Jan 2. pii: S0896-6273(19)31056-6. doi: 10.1016/j.neuron.2019.12.014.
Other news:
- Giovanna has received a donation from the Frances and Augustus Newman Foundation to fund two translational postgraduate scholarship between the UK DRI and Dept. Chemistry at the University of Cambridge.
- Dr. Adrian Butcher has received an UK DRI pilot award
Please see my google scholar profile for a full publication list.
- Halliday M, Radford H, Zents KAM, Verity NC, Smith E, Ortori CA, Barrett DA, Bushell M and Mallucci GR. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain 2017, 140(6):1768-1783.
- Radford H, Moreno JA, Verity N, Halliday M and Mallucci GR. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathologica. 2015 Nov;130(5):633-42.
- Halliday M, Radford H, Sekine Y, Moreno JA, Verity N, le Quesne J, Ortori CA, Barrett DA, Fromont C, Fischer PM, Harding HP, Ron D and Mallucci GR. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death & Disease 2015 6:e1672.
- Peretti D, Bastide A, Verity N, Guerra Martin M, Molloy C, Moreno JA, Radford H, Steinert J, Dinsdale D, Willis AE and Mallucci GR. RBM3 mediates structural plasticity and the protective effects of cooling in neurodegenerative disease. Nature 2015 518(7538):236-9.
- Moreno JA, Halliday M, Molloy C, Axten JM, Willis AE, Ortori CA, Barrett DA, Fischer PM and Mallucci GR. Oral treatment targeting the unfolded protein response prevents prion neurodegeneration and clinical disease in mice. Science Translational Medicine, 2013, 5,206ra138.
- Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Guerra Martin M, Halliday M, Morgan J, Dinsdale D, Ortori CA, Barrett DA, Tsaytler P, Bertolotti A, Willis AE, M Bushell and Mallucci GR. Sustained translational repression by eIF2α−P mediates prion neurodegeneration. Nature 2012, 485, 507-11
